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AIDS:
Editorial Comment

Reassessing the goal of antiretroviral therapy in the heavily pre-treated HIV-infected patient

Deeks, Steven G.; Martin, Jeffrey N.a

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From the Department of Medicine, and the aDepartment of Epidemiology and Biostatistics and of Medicine, University of California, San Francisco and San Francisco General Hospital, San Francisco, California, USA.

Received: 25 October 2000; accepted: 26 October 2000.

Sponsorship: Supported in part by grants from the California AIDS Research Center (CC99-SF-001) and the University of California, San Francisco Center for AIDS Research (P30 MH59037).

Requests for reprints to: S. G. Deeks, 995 Potrero Avenue, San Francisco General Hospital, San Francisco, CA 94110, USA.

Failure of combination antiretroviral therapy to completely and durably suppress HIV replication is common in clinical practice [1–3]. Although this has been widely known since 1997, the optimal therapeutic approach to virologic failure has not been defined. Published clinical guidelines recommend that patients switch to an entirely new regimen as soon as virologic failure is confirmed, and that complete viral suppression remain the goal of therapy [4,5]. Yet, clinicians have long realized that this approach often fails to achieve durable viral suppression, especially in heavily pre-treated patients. Recent clinical trials have failed to establish a standard approach for the previously treated patient population [6].

Much of the uncertainty surrounding the management of the treatment-experienced patient relates to the observation that virologic failure, defined simply as detectable viremia, rarely results in immediate immunologic and clinical failure [7–9]. Patients who continue a protease inhibitor-based regimen despite ongoing viral replication often maintain some degree of partial viral suppression. As a result, CD4 T cell counts increase and remain elevated [9]. When patients experiencing prolonged virologic failure discontinue therapy, viral replication increases and CD4 T cell counts decrease, thereby indicating that the ‘failing’ regimen was indeed providing benefit [10]. These observations suggest that patients with limited therapeutic options may achieve durable immunologic and clinical benefit from strategies aimed at maintaining partial viral suppression.

Working under the assumption that complete viral suppression should remain the goal of antiretroviral therapy for all patients, Montaner and colleagues pursued an aggressive strategy which they term ‘multiple drug rescue therapy', popularly known as ‘mega-HAART’[11]. In an uncontrolled trial, they administered between five and nine antiretroviral agents to 106 heavily pre-treated patients. The regimens were often very complex and included up to four nucleoside reverse transcriptase inhibitors, two protease inhibitors, two non-nucleoside reverse transcriptase inhibitors, and hydroxyurea. When all patients were considered in an intention-to-treat analysis, approximately 28% achieved a plasma viral load of less than 50 copies/ml at 1 year of observation.

What might account for the higher than anticipated percentage of patients who achieved an undetectable viral load? First, drug resistance is not an all-or-none phenomenon. Indeed the term ‘reduced drug susceptibility’ is preferred over ‘drug resistance’ because it implies that antiretroviral drugs retain partial activity even after the emergence of specific mutations. Second, incomplete viral suppression in the face of ongoing drug pressure selects for mutations that may impact negatively on viral replicative capacity (`viral fitness') [12,13]. The simultaneous use of multiple antiretroviral agents may select for a viral population that is highly drug-resistant yet can only replicate at low levels. Third, countless HIV variants may emerge during incomplete viral suppression [13], each with its own pattern of reduced drug susceptibilities. Administering as many drugs as possible increases the likelihood that all viral strains will be suppressed. Finally, the relative ability of each antiretroviral agent to penetrate tissue sanctuaries varies. Administering multiple agents increases the likelihood that all viruses will be exposed to effective drug concentrations. Understanding how each of these related factors influences the virologic response to therapy should be a research priority.

Montaner and colleagues were able to demonstrate the principle that some heavily pre-treated patients are able to achieve virologic success with multiple drug rescue therapy, but questions remain as to whether this is a clinically useful strategy. First, simpler and more tolerable regimens may have been available for many heavily pre-treated patients. Sixty percent of the group studied by Montaner was non-nucleoside reverse transcriptase inhibitor naive. Such patients often do well with simpler and less toxic regimens such as those containing one non-nucleoside reverse transcriptase inhibitor and two protease inhibitors [6]. Furthermore, as Montaner and colleagues discuss, the advent of resistance testing, which allows strategic choice of specific agents to which a virus demonstrates susceptibility, may have rendered multiple drug rescue therapy obsolete. For example, if the three or four agents demonstrating the most susceptibility have efficacy equal to a nine-drug regimen, then the simpler regimen would be preferable.

Second, the toxicity associated with multiple drug rescue therapy will probably limit its use severely. For example, gastrointestinal complaints were reported by 45% of those treated in the current study. Not only does this impact quality of life but may also, in time, threaten adherence which in turn results in incomplete drug exposure and emergence of drug resistance – the very outcome that multiple drug rescue therapy was intended to prevent. A related issue that may limit clinical use, although not relevant in all settings, is the cost of regimens containing up to nine drugs.

Third, and most important, is whether multiple drug rescue therapy will impact clinically relevant outcomes. At this time, without the availability of controlled trials that follow patients for both morbidity and mortality, the answer to this question is not known. However, the failure of multiple drug rescue therapy to increase CD4 T cell counts, even in those patients in whom an undetectable viral load was obtained, suggests that a clinical benefit may not have been achieved. This is substantiated by the two instances of AIDS-defining diagnoses and seven deaths that occurred during the study. Of note, this high clinical event rate suggests that controlled trials of multiple drug rescue therapy with clinical outcomes may not require unduly large sample sizes.

That a clinical benefit may not have been achieved with multi-drug rescue therapy calls into question the current wisdom of deeming an undetectable viral load the goal of therapy in the heavily pre-treated population. Even if it can be accepted that an undetectable viral load is an appropriate surrogate marker for clinically relevant outcomes in treatment-inexperienced patients who are initiating combination therapy, it cannot necessarily be accepted without proof that it is a useful surrogate in heavily pre-treated patients. This is both because the virus in heavily pre-treated patients may be different from wild-type virus (for example, in replicative fitness as discussed above) and because the complex regimens required to achieve an undetectable viral load may have negative impacts on patient health.

Therefore, until controlled trials are able to prove the utility of an undetectable viral load as a surrogate marker for clinically relevant outcomes in heavily pre-treated patients, we believe that clinicians should show caution before striving for complete viral suppression at any cost. Until more is known, alternative goals of therapy that emphasize partial virologic suppression and immunologic benefit deserve equal consideration.

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References

1. Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med 1999, 131: 81 –87.

2. Fatkenheuer G, Theisen A, Rockstroh J. et al. Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. AIDS 1997, 11: F113 –F116.

3. Deeks SG, Hecht FM, Swanson M. et al. Virologic outcomes with protease inhibitor therapy in an urban AIDS clinic: relationship between baseline characteristics and response to both initial and salvage therapy. AIDS 1999, 13: F35 –F44.

4. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. http://www.hivatis.org [accessed 28 January 2000].

5. Carpenter CC, Cooper DA, Fischl M. et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel. JAMA 2000, 283: 381 –390.

6. Gulick RM, Hu XJ, Fiscus SA. et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group study 359. J Infect Dis 2000, 182: 1375 –1384.

7. Ledergerber B, Egger M, Opravil M. et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 1999, 353: 863 –868.

8. Grabar S, Le Moing V, Goujard C. et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med 2000, 133: 401 –411.

9. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4 T cell response after virologic failure of protease inhibitor based regimens in HIV infected patients. J Infect Dis 2000, 181: 946 –953.

10. Miller V, Sabin C, Hertogs K. et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 2000, 14: 2857 –2867.

11. Montaner JSG, Harrigan PR, Jahnke N. et al. Multiple drug rescue therapy (MDRT) for HIV-infected individuals with prior virologic failure to multiple regimens. AIDS 2000, 15: 63 –71.

12. Martinez-Picado J, Savara AV, Sutton L, D'Aquila RT. Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol 1999, 73: 3744 –3752.

13. Coffin JM. HIV population dynamicsin vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995, 267: 483 –489.

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Keywords:

Antiretroviral therapy; multiple drug rescue therapy; HIV drug resistance; HIV; AIDS

© 2001 Lippincott Williams & Wilkins, Inc.

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